Microvascular and Antiinflammatory Effects of Rivaroxaban... | NCT02164578

Label	Type	Description	Intervention Names
Rivaroxaban	Experimental	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)	Drug: Rivaroxaban
Aspirin	Active Comparator	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)	Drug: Aspirin

Name	Type	Description	Arm Group Labels	Other Names
Rivaroxaban	Drug		Rivaroxaban
Aspirin

Measure	Description	Time Frame
Change in Post-ischemic Forearm Blood Flow	Change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml). Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 20 weeks treatment with rivaroxaban or aspirin.	Baseline and week 20
Change in Pulse Wave Velocity	Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph)	Baseline and week 52

Measure	Description	Time Frame
Change in Post-ischemic Forearm Blood Flow	Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 52 weeks treatment with rivaroxaban or aspirin.	Baseline and week 52
Change in Pulse Wave Velocity

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Type 2 diabetes duration between 2 and 20 years
Two or more components of metabolic syndrome:
- HDL-cholesterol < 1.0 mmol/L (in males) or < 1.3 mmol/L (in females)
- Elevated triglycerides (> 1.7 mmol/L)
- Elevated blood pressure (> 130 mmHg systolic and/or >85 mmHg diastolic or antihypertensive treatment)
- Elevated waist circumference (> 102 cm in males, > 85 cm in females)
Or at least one of the following
- Carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or
- Left ventricular hypertrophy or
- Increased UACR in the absence of other renal diseases than diabetic nephropathy
Increased hsCRP (> 2 mg/l but < 10 mg/l) at or within 6 months prior to screening and/or increased PAI 1 (> 15 ng/ml) at or within 6 months prior to screening (the historical hsCRP or PAI 1 value can be used only if the patient was in stable conditions regarding the concomitant diseases and statin therapy since the time point of measurement)
Stable treatment with statins (if tolerated/clinically indicated)
Age 40 - 75 years

Exclusion Criteria:

Major cardiovascular (CV) event with need for oral anticoagulation or platelet inhibitor therapy or acute coronary syndrome < 12 month before study entry
Sustained uncontrolled hypertension: systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg
Hypersensitivity to the active substance or to any of the excipients
Active clinically significant bleeding
Lesion or condition, if considered to be a significant risk for major bleeding
Concomitant treatment of acute coronary syndrome (ACS) with antiplatelet therapy in patients with a prior stroke or a transient ischemic attack (TIA)
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
Chronic renal failure with eGFR < 15 ml/min (MDRD formula)
Pregnant or breast-feeding woman and woman without adequate method of contraception.

Name	Affiliation	Role
Frank Pistrosch, Dr. med.	GWT-TUD GmbH	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Krankenhaus Dresden-Friedrichstadt		Dresden	Saxony	01067	Germany
Universitätsmedizin Berlin / Charité Campus Buch

PubMed Identifier	Type	Citation	Retractions
34495376	Derived	Pistrosch F, Matschke JB, Schipp D, Schipp B, Henkel E, Weigmann I, Sradnick J, Bornstein SR, Birkenfeld AL, Hanefeld M. Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers. Diabetologia. 2021 Dec;64(12):2701-2712. doi: 10.1007/s00125-021-05562-9. Epub 2021 Sep 8.

ID	Title	Description
FG000	Rivaroxaban	5mg b.i.d. for 20 weeks (treatment phase) + additional 32 weeks (extension phase)
FG001	Aspirin	100mg once daily for 20 weeks (treatment phase) + additional 32 weeks (extension phase)

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 7, 2016	Feb 24, 2021

ID	Title	Description
BG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
BG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00089 BG00190 BG002179

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in Post-ischemic Forearm Blood Flow

Change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml).

Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 20 weeks treatment with rivaroxaban or aspirin.

Full Analysis Set

Posted

Mean

Standard Deviation

ml/100ml

Baseline and week 20

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG00083 OG00184

Title

Denominators

Categories

Title	Measurements
	OG0003.60± 4.69 OG0011.00± 5.27

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The hypothesis H0 is tested against the one-sided alternative hypothesis H1 H0: µ∆FBF,Riva, week 20 ≤ µ∆FBF, ASA, week 20 versus H1: µΔFBF, Riva, week 20 > µΔFBF, ASA, week 20 by test procedures for continuous data.	ANCOVA	ANCOVA for repeated measurements with baseline as covariate	0.004														Superiority

Primary

Change in Pulse Wave Velocity

Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph)

Full Analysis Set of the extension phase

Posted

Mean

Standard Deviation

m/s

Baseline and week 52

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Change in Post-ischemic Forearm Blood Flow

Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 52 weeks treatment with rivaroxaban or aspirin.

Full Analysis Set of the extension phase

Posted

Mean

Standard Deviation

ml/100ml

Baseline and week 52

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Change in Pulse Wave Velocity

Change in pulse wave velocity as a marker for arterial stiffness (measured by IEM Mobil-O-Graph)

Full Analysis Set

Posted

Mean

Standard Deviation

m/s

Baseline to week 20

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Change in Skin Blood Flow

Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)

Full Analysis Set

Posted

Mean

Standard Deviation

arbitrary units

Baseline to week 20

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Change in Skin Blood Flow

Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)

Full Analysis Set of the extension phase

Posted

Mean

Standard Deviation

arbitrary units

Baseline to week 52

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Major Bleeding

Major bleeding defined as clinically overt and associated with one of the following: 1) reduction of hemoglobin level of 2 g/L or 2) required transfusion of at least 2 units of red cells or, involved a critical organ or was fatal, in accordance with the recommendation of the International Society on Thrombosis and Hemostasis (ISTH).

Safety Analysis Set

Posted

Number

events

Week 1 to week 20

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Major Bleeding

Safety Analysis Set of the extension phase

Posted

Number

events

Week 1 to week 52

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants	OG000

Secondary

Clinically Relevant Non-major (CRNM) Bleeding

Clinically relevant non-major (CRNM) bleeding defined as at least one of the following:

spontaneous skin hematoma of at least 25 cm
spontaneous nose bleeding of more than 5 minutes duration
macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours
spontaneous rectal bleeding (more than spotting on toilet paper)
gingival bleeding for more than 5 minutes
bleeding leading to hospitalization and/or requiring surgical treatment
bleeding leading to a transfusion of less than 2 units of whole blood or red cells
any other bleeding event considered clinically relevant by the investigator

Safety Analysis Set

Posted

Number

events

Week 1 to week 20

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants

Secondary

Clinically Relevant Non-major (CRNM) Bleeding

Clinically relevant non-major (CRNM) bleeding defined as at least one of the following:

spontaneous skin hematoma of at least 25 cm
spontaneous nose bleeding of more than 5 minutes duration
macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours
spontaneous rectal bleeding (more than spotting on toilet paper)
gingival bleeding for more than 5 minutes
bleeding leading to hospitalization and/or requiring surgical treatment
bleeding leading to a transfusion of less than 2 units of whole blood or red cells
any other bleeding event considered clinically relevant by the investigator

Safety Analysis Set of the extension phase

Posted

Number

events

Week 1 to week 52

ID	Title	Description
OG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)
OG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)

Units	Counts
Participants

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Gastrointestinal hemorrhage	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Chest pain	General disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Bile duct stone	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Diverticulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Erysipelas	Infections and infestations	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Escherichia sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 events1 affected89 at risk EG0010 events0 affected90 at risk
Foot fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0011 events1 affected90 at risk
Syncope	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Ovarian cyst	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Hysterectomy	Surgical and medical procedures	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Joint arthroplasty	Surgical and medical procedures	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG0001 events1 affected89 at risk EG0010 events0 affected90 at risk
Hypertensive crisis	Vascular disorders	MedDRA	Systematic Assessment	EG0000 events0 affected89 at risk EG0013 events2 affected90 at risk

ID	Term
D013876	Thiophenes
D013457	Sulfur Compounds
D009930	Organic Chemicals
D009025	Morpholines
D010078	Oxazines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D012459	Salicylates
D062385	Hydroxybenzoates
D010636	Phenols
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Rivaroxaban	5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)	0	89	4	89	0	89
EG001	Aspirin	100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)	0	90	6	90	0	90